Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability.
The Sonic Hedgehog (Shh) pathway plays important roles in embryogenesis, stem cell maintenance, tissue repair, and tumorigenesis. Haploinsufficiency of Patched-1, a gene that encodes a repressor of the Shh pathway, dysregulates the Shh pathway and increases genomic instability and the development of spontaneous and ionizing radiation (IR)-induced tumors by an unknown mechanism. Here we show that Ptc1(+/-) mice have a defect in the IR-induced activation of the ATR-Chk1 checkpoint signaling pathway. Likewise, transient expression of Gli1, a downstream target of Shh signaling, disrupts Chk1 activation in human cells by preventing the interaction of Chk1 with Claspin, a Chk1 adaptor protein that is required for Chk1 activation. These results suggest that inappropriate Shh pathway activation promotes tumorigenesis by disabling a key signaling pathway that helps maintain genomic stability and inhibits tumorigenesis.
Leonard
Jennifer M
JM
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Ye
Hong
H
Wetmore
Cynthia
C
Karnitz
Larry M
LM
D000818:Animals; D002528:Cerebellar Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004277:DNA, Single-Stranded / Q000235:genetics / Q000528:radiation effects; D042822:Genomic Instability / Q000235:genetics* / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology; D008527:Medulloblastoma / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011839:Radiation, Ionizing; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics*; D000071676:Zinc Finger Protein GLI1
D004277:DNA, Single-Stranded; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases